SECOND AMENDMENT TO THE PRODUCT DEVELOPMENT AND COMMERCIALIZATION AGREEMENT BETWEEN SMITHKLINE BEECHAM CORPORATION D/B/A GLAXOSMITHKLINE AND EXELIXIS, INC.

Exhibit 10.3

EXECUTION

SECOND AMENDMENT TO THE PRODUCT DEVELOPMENT AND

COMMERCIALIZATION AGREEMENT BETWEEN SMITHKLINE BEECHAM

CORPORATION D/B/A GLAXOSMITHKLINE AND EXELIXIS, INC. DATED

AS OF OCTOBER 28, 2002.

This S ECOND A MENDMENT (the “ Second Amendment ”) is entered into as of June 13, 2008 (the “ Second Amendment Effective Date ”), by and between S MITH K LINE B EECHAM C ORPORATION , a Pennsylvania corporation, doing business as GlaxoSmithKline (“ GSK ”), and E XELIXIS , I NC . , a Delaware corporation (“ EXEL ”). EXEL and GSK are each referred to herein individually as a “ Party ” or, collectively, as the “ Parties .”

R ECITALS

W HEREAS , the Parties entered into that certain Product Development and Commercialization Agreement dated as of October 28, 2002, and as amended by the Parties on January 10, 2005 (collectively, the “ Development Agreement ”) under which EXEL and GSK formed a broad alliance to discover, develop and commercialize novel therapeutics; and

W HEREAS , the Parties now desire to amend certain provisions of the Development Agreement as set forth below in this Second Amendment.

N OW , T HEREFORE , in consideration of the premises and mutual covenants herein contain, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties hereto agree as follows:

A GREEMENT

The Parties hereby agree to amend the terms of the Development Agreement as provided below, effective as of the Second Amendment Effective Date. To the extent that the Development Agreement is explicitly amended by this Second Amendment, the terms of this Second Amendment will control where the terms of the Development Agreement are contrary to or conflict with the following provisions. Where the Development Agreement is not explicitly amended, the terms of the Development Agreement will remain in full force and effect. Capitalized terms used in this Second Amendment that are not otherwise defined herein shall have the same meanings as such terms are defined in the Development Agreement.

1.1 Amendment of Section 1.29. Section 1.29 is hereby deleted in its entirety and replaced with the following:

“1.29 [Intentionally left blank.]”

[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24B-2 of the Securities Exchange Act of 1934, as amended.

1.2 Amendment of Section 1.94. Section 1.94 is hereby deleted in its entirety and replaced with the following:

“1.94 [Intentionally left blank.]”

1.3 Amendment of Section 1.118. Section 1.118 is hereby deleted in its entirety and replaced with the following:

“1.118 “ Product ” shall mean, [ * ].”

1.4 Amendment of Section 3.9. Section 3